Screening remains a major bottleneck in the discovery of new enzymes, protein therapeutics, and small molecule drugs. Many important high-value bioactives have yet to be discovered. This project is aimed at overcoming functional and throughput limitations of conventional screening methodologies by demonstrating the feasibility of a million-well screening platform for the discovery of rare bioactives from complex environmental gene libraries. Diversa's 100,000-well GigaMatrixTM platform has been successfully utilized to discover novel enzymes by expression screening. We now propose to make a significant advance in this approach to screening. By using million-well plates, we are aiming at screening throughputs of one billion clones per day using standard liquid-phase fluorescent assays. The necessity for this innovation derives from the requirement to screen complex, multi-organism (10 to the power of 7 to 10 to the power of 10) DNA libraries generated both from primary environmental samples and from laboratory evolution techniques. Furthermore, this development enables not only the discovery of rare novel enzymes but also antibody and protein therapeutic programs that require rapid screening of libraries with 10 to the power of 8 to 10 to the power of 9 antibody and protein variants. Commercialization of both bioactive molecules derived from screening and the GigaMatrix million-well technology itself is envisioned, each representing a significant contribution to the synthesis of new pharmaceuticals and therapeutics.